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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Feb 1;90(3):923–927. doi: 10.1073/pnas.90.3.923

Clonal expansions of activated gamma/delta T cells in recent-onset multiple sclerosis.

R Shimonkevitz 1, C Colburn 1, J A Burnham 1, R S Murray 1, B L Kotzin 1
PMCID: PMC45782  PMID: 8430106

Abstract

Multiple sclerosis (MS) is a chronic disease characterized by focal demyelination of the white matter of the brain and spinal cord. Central nervous system damage appears to be mediated by infiltrating T lymphocytes and macrophages, and a central role for autoreactive CD4+ T cells has been proposed. However, the initial immune events that lead to the chronic process of MS remain unidentified. We now present evidence that a subset of T lymphocytes bearing gamma/delta T-cell antigen receptors has been activated in patients with recent-onset disease. Cells recovered from the cerebrospinal fluid of subjects with MS were cultured for short periods of time in medium supplemented with T-cell growth factors. Expansions of V delta 1 and V delta 2 T-cell receptor-bearing lymphocytes were found only in cell populations obtained from subjects with recent-onset disease. Similar populations were not expanded in subjects with chronic MS or other neurological diseases. Junctional region sequencing showed the expanded gamma/delta T cells to be oligoclonal in nature, suggestive of specific stimulation by antigen. These results reveal a fundamental difference in the immunopathogenesis of acute vs. chronic disease and provide additional insight into the autoimmune nature of MS.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Balbi B., Moller D. R., Kirby M., Holroyd K. J., Crystal R. G. Increased numbers of T lymphocytes with gamma delta-positive antigen receptors in a subgroup of individuals with pulmonary sarcoidosis. J Clin Invest. 1990 May;85(5):1353–1361. doi: 10.1172/JCI114579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bellamy A. S., Calder V. L., Feldmann M., Davison A. N. The distribution of interleukin-2 receptor bearing lymphocytes in multiple sclerosis: evidence for a key role of activated lymphocytes. Clin Exp Immunol. 1985 Aug;61(2):248–256. [PMC free article] [PubMed] [Google Scholar]
  3. Ben-Nun A., Liblau R. S., Cohen L., Lehmann D., Tournier-Lasserve E., Rosenzweig A., Zhang J. W., Raus J. C., Bach M. A. Restricted T-cell receptor V beta gene usage by myelin basic protein-specific T-cell clones in multiple sclerosis: predominant genes vary in individuals. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2466–2470. doi: 10.1073/pnas.88.6.2466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Born W. K., O'Brien R. L., Modlin R. L. Antigen specificity of gamma delta T lymphocytes. FASEB J. 1991 Sep;5(12):2699–2705. doi: 10.1096/fasebj.5.12.1717333. [DOI] [PubMed] [Google Scholar]
  5. Borst J., van Dongen J. J., Bolhuis R. L., Peters P. J., Hafler D. A., de Vries E., van de Griend R. J. Distinct molecular forms of human T cell receptor gamma/delta detected on viable T cells by a monoclonal antibody. J Exp Med. 1988 May 1;167(5):1625–1644. doi: 10.1084/jem.167.5.1625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Choi Y. W., Herman A., DiGiusto D., Wade T., Marrack P., Kappler J. Residues of the variable region of the T-cell-receptor beta-chain that interact with S. aureus toxin superantigens. Nature. 1990 Aug 2;346(6283):471–473. doi: 10.1038/346471a0. [DOI] [PubMed] [Google Scholar]
  7. Ciccone E., Ferrini S., Bottino C., Viale O., Prigione I., Pantaleo G., Tambussi G., Moretta A., Moretta L. A monoclonal antibody specific for a common determinant of the human T cell receptor gamma/delta directly activates CD3+WT31- lymphocytes to express their functional program(s). J Exp Med. 1988 Jul 1;168(1):1–11. doi: 10.1084/jem.168.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. De Libero G., Casorati G., Giachino C., Carbonara C., Migone N., Matzinger P., Lanzavecchia A. Selection by two powerful antigens may account for the presence of the major population of human peripheral gamma/delta T cells. J Exp Med. 1991 Jun 1;173(6):1311–1322. doi: 10.1084/jem.173.6.1311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. De Paoli P., Gennari D., Martelli P., Cavarzerani V., Comoretto R., Santini G. Gamma delta T cell receptor-bearing lymphocytes during Epstein-Barr virus infection. J Infect Dis. 1990 May;161(5):1013–1016. doi: 10.1093/infdis/161.5.1013. [DOI] [PubMed] [Google Scholar]
  10. Fisch P., Malkovsky M., Kovats S., Sturm E., Braakman E., Klein B. S., Voss S. D., Morrissey L. W., DeMars R., Welch W. J. Recognition by human V gamma 9/V delta 2 T cells of a GroEL homolog on Daudi Burkitt's lymphoma cells. Science. 1990 Nov 30;250(4985):1269–1273. doi: 10.1126/science.1978758. [DOI] [PubMed] [Google Scholar]
  11. Goodkin D. E., Doolittle T. H., Hauser S. S., Ransohoff R. M., Roses A. D., Rudick R. A. Diagnostic criteria for multiple sclerosis research involving multiply affected families. Arch Neurol. 1991 Aug;48(8):805–807. doi: 10.1001/archneur.1991.00530200041016. [DOI] [PubMed] [Google Scholar]
  12. Hohlfeld R., Engel A. G., Ii K., Harper M. C. Polymyositis mediated by T lymphocytes that express the gamma/delta receptor. N Engl J Med. 1991 Mar 28;324(13):877–881. doi: 10.1056/NEJM199103283241303. [DOI] [PubMed] [Google Scholar]
  13. Holoshitz J., Koning F., Coligan J. E., De Bruyn J., Strober S. Isolation of CD4- CD8- mycobacteria-reactive T lymphocyte clones from rheumatoid arthritis synovial fluid. Nature. 1989 May 18;339(6221):226–229. doi: 10.1038/339226a0. [DOI] [PubMed] [Google Scholar]
  14. Howell M. D., Diveley J. P., Lundeen K. A., Esty A., Winters S. T., Carlo D. J., Brostoff S. W. Limited T-cell receptor beta-chain heterogeneity among interleukin 2 receptor-positive synovial T cells suggests a role for superantigen in rheumatoid arthritis. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10921–10925. doi: 10.1073/pnas.88.23.10921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Janis E. M., Kaufmann S. H., Schwartz R. H., Pardoll D. M. Activation of gamma delta T cells in the primary immune response to Mycobacterium tuberculosis. Science. 1989 May 12;244(4905):713–716. doi: 10.1126/science.2524098. [DOI] [PubMed] [Google Scholar]
  16. Johnson R. M., Lancki D. W., Sperling A. I., Dick R. F., Spear P. G., Fitch F. W., Bluestone J. A. A murine CD4-, CD8- T cell receptor-gamma delta T lymphocyte clone specific for herpes simplex virus glycoprotein I. J Immunol. 1992 Feb 15;148(4):983–988. [PubMed] [Google Scholar]
  17. Kabelitz D., Bender A., Prospero T., Wesselborg S., Janssen O., Pechhold K. The primary response of human gamma/delta + T cells to Mycobacterium tuberculosis is restricted to V gamma 9-bearing cells. J Exp Med. 1991 Jun 1;173(6):1331–1338. doi: 10.1084/jem.173.6.1331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kotzin B. L., Karuturi S., Chou Y. K., Lafferty J., Forrester J. M., Better M., Nedwin G. E., Offner H., Vandenbark A. A. Preferential T-cell receptor beta-chain variable gene use in myelin basic protein-reactive T-cell clones from patients with multiple sclerosis. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9161–9165. doi: 10.1073/pnas.88.20.9161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Krangel M. S., Yssel H., Brocklehurst C., Spits H. A distinct wave of human T cell receptor gamma/delta lymphocytes in the early fetal thymus: evidence for controlled gene rearrangement and cytokine production. J Exp Med. 1990 Sep 1;172(3):847–859. doi: 10.1084/jem.172.3.847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lang F. P., Schatz D. A., Pollock B. H., Riley W. J., Maclaren N. K., Dumont-Driscoll M., Barrett D. J. Increased T lymphocytes bearing the gamma-delta T cell receptor in subjects at high risk for insulin dependent diabetes. J Autoimmun. 1991 Dec;4(6):925–933. doi: 10.1016/0896-8411(91)90055-h. [DOI] [PubMed] [Google Scholar]
  21. Lanier L. L., Ruitenberg J., Bolhuis R. L., Borst J., Phillips J. H., Testi R. Structural and serological heterogeneity of gamma/delta T cell antigen receptor expression in thymus and peripheral blood. Eur J Immunol. 1988 Dec;18(12):1985–1992. doi: 10.1002/eji.1830181218. [DOI] [PubMed] [Google Scholar]
  22. Martin R., McFarland H. F., McFarlin D. E. Immunological aspects of demyelinating diseases. Annu Rev Immunol. 1992;10:153–187. doi: 10.1146/annurev.iy.10.040192.001101. [DOI] [PubMed] [Google Scholar]
  23. McFarlin D. E., Lachmann P. J. Multiple sclerosis. Hopeful genes and immunology. Nature. 1989 Oct 26;341(6244):693–694. doi: 10.1038/341693a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Modlin R. L., Pirmez C., Hofman F. M., Torigian V., Uyemura K., Rea T. H., Bloom B. R., Brenner M. B. Lymphocytes bearing antigen-specific gamma delta T-cell receptors accumulate in human infectious disease lesions. Nature. 1989 Jun 15;339(6225):544–548. doi: 10.1038/339544a0. [DOI] [PubMed] [Google Scholar]
  25. Ohga S., Yoshikai Y., Takeda Y., Hiromatsu K., Nomoto K. Sequential appearance of gamma/delta- and alpha/beta-bearing T cells in the peritoneal cavity during an i.p. infection with Listeria monocytogenes. Eur J Immunol. 1990 Mar;20(3):533–538. doi: 10.1002/eji.1830200311. [DOI] [PubMed] [Google Scholar]
  26. Oksenberg J. R., Stuart S., Begovich A. B., Bell R. B., Erlich H. A., Steinman L., Bernard C. C. Limited heterogeneity of rearranged T-cell receptor V alpha transcripts in brains of multiple sclerosis patients. Nature. 1990 May 24;345(6273):344–346. doi: 10.1038/345344a0. [DOI] [PubMed] [Google Scholar]
  27. Poser C. M., Paty D. W., Scheinberg L., McDonald W. I., Davis F. A., Ebers G. C., Johnson K. P., Sibley W. A., Silberberg D. H., Tourtellotte W. W. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983 Mar;13(3):227–231. doi: 10.1002/ana.410130302. [DOI] [PubMed] [Google Scholar]
  28. Raulet D. H. The structure, function, and molecular genetics of the gamma/delta T cell receptor. Annu Rev Immunol. 1989;7:175–207. doi: 10.1146/annurev.iy.07.040189.001135. [DOI] [PubMed] [Google Scholar]
  29. Selmaj K., Brosnan C. F., Raine C. S. Colocalization of lymphocytes bearing gamma delta T-cell receptor and heat shock protein hsp65+ oligodendrocytes in multiple sclerosis. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6452–6456. doi: 10.1073/pnas.88.15.6452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Selmaj K., Brosnan C. F., Raine C. S. Expression of heat shock protein-65 by oligodendrocytes in vivo and in vitro: implications for multiple sclerosis. Neurology. 1992 Apr;42(4):795–800. doi: 10.1212/wnl.42.4.795. [DOI] [PubMed] [Google Scholar]
  31. Stamenkovic I., Stegagno M., Wright K. A., Krane S. M., Amento E. P., Colvin R. B., Duquesnoy R. J., Kurnick J. T. Clonal dominance among T-lymphocyte infiltrates in arthritis. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1179–1183. doi: 10.1073/pnas.85.4.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Terasaki P. I., Park M. S., Opelz G., Ting A. Multiple sclerosis and high incidence of a B lymphocyte antigen. Science. 1976 Sep 24;193(4259):1245–1247. doi: 10.1126/science.1085490. [DOI] [PubMed] [Google Scholar]
  33. Traugott U., Reinherz E. L., Raine C. S. Multiple sclerosis: distribution of T cell subsets within active chronic lesions. Science. 1983 Jan 21;219(4582):308–310. doi: 10.1126/science.6217550. [DOI] [PubMed] [Google Scholar]
  34. Van Wauwe J. P., De Mey J. R., Goossens J. G. OKT3: a monoclonal anti-human T lymphocyte antibody with potent mitogenic properties. J Immunol. 1980 Jun;124(6):2708–2713. [PubMed] [Google Scholar]
  35. Waksman B. Mechanisms in multiple sclerosis. Nature. 1985 Nov 14;318(6042):104–105. doi: 10.1038/318104a0. [DOI] [PubMed] [Google Scholar]
  36. Wu Y. J., Tian W. T., Snider R. M., Rittershaus C., Rogers P., LaManna L., Ip S. H. Signal transduction of gamma/delta T cell antigen receptor with a novel mitogenic anti-delta antibody. J Immunol. 1988 Sep 1;141(5):1476–1479. [PubMed] [Google Scholar]
  37. Wucherpfennig K. W., Newcombe J., Li H., Keddy C., Cuzner M. L., Hafler D. A. Gamma delta T-cell receptor repertoire in acute multiple sclerosis lesions. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4588–4592. doi: 10.1073/pnas.89.10.4588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wucherpfennig K. W., Ota K., Endo N., Seidman J. G., Rosenzweig A., Weiner H. L., Hafler D. A. Shared human T cell receptor V beta usage to immunodominant regions of myelin basic protein. Science. 1990 May 25;248(4958):1016–1019. doi: 10.1126/science.1693015. [DOI] [PubMed] [Google Scholar]
  39. van de Griend R. J., Borst J., Tax W. J., Bolhuis R. L. Functional reactivity of WT31 monoclonal antibody with T cell receptor-gamma expressing CD3+4-8- T cells. J Immunol. 1988 Feb 15;140(4):1107–1110. [PubMed] [Google Scholar]

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